Our goal is to determine whether changes in the formation or processing of oxidative DNA damage are associated with neurodegeneration observed after stroke or in aging and age-associated diseases. Stroke is a leading cause of death, and ROS generated during ischemia may contribute to neuronal death. Although stroke is treatable with timely medical help, only 10% of stroke victims recover completely from a major stroke episode. Thus, it is important not only to identify risk factors for stroke, but to identify factors that influence post-stroke outcomes (i.e., reduce disability or death from stroke). It has been proposed that lower BER capacity could partly explain the increased incidence and adverse effects of stroke in older individuals. Therefore, we are investigating the impact of simulated stroke in mice carrying defects in specific DNA glycosylases or other BER enzymes. We are testing the hypothesis that loss of BER capacity negatively impacts the brains ability to recover from acute oxidative stress experienced during a stroke. Using the Ogg1 knockout mice and a stroke model, we previously demonstrated that Ogg1 KO animals had larger infarct volumes and displayed poor recovery following stroke. Our recent results suggest that the Neil1 KO mice are more sensitive to stroke and generates more ischemia and recovers more slowly than wild type mice. In addition, using behavioral studies, we detected a memory deficiency in the Neil1 KO mice. This work suggests that a BER deficiency may be directly associated with cognitive function and we plan to extend these studies to other DNA repair defective mouse models and on another genetic background. Together, these findings underscore the importance of BER as a disease modifier. Efforts to define other BER proteins whose absence impacts the recovery from stroke are ongoing and continue to support our findings that an individual's BER capacity may be a major determinant in the extent of recovery from an acute stressor like stroke. AD is one of the leading causes of neurodegeneration and there are numerous documented cases of neurodegeneration associated with genetic DNA repair defects. Given that there is compelling evidence that DNA repair capacity alters the ability of mice to recover from an acute oxidative stress and that AD is associated with chronic oxidative stress, we tested the hypothesis that a defect in DNA repair might exacerbate the AD phenotypes in a mouse model of AD (3xTg AD). While the studies are still ongoing, there is evidence to suggest that a defect in DNA repair capacity can modulate memory and learning. Full behavioral, memory and learning experiments are underway in mice to quantify the extent to which a DNA repair deficiency impacts the AD features.